Genetically engineered macrophages to treat pulmonary infections

基因工程巨噬细胞治疗肺部感染

• 批准号: 9977009
• 负责人: Courtney Crane
• 金额: $ 27.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-06 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977009
• 关键词: Acute; Adoptive Transfer; Anti-Bacterial Agents; Antibiotics; Antibodies; Antimicrobial Resistance; Australia; Bacterial Model; Bacterial Pneumonia; Bacterial Proteins; Biological Response Modifiers; Biology; Bone Marrow; Brain Neoplasms; Burkholderia pseudomallei; CD19 gene; Cells; Cellular immunotherapy; Cephalosporins; Cessation of life; Clinical Trials; Community Healthcare; Development; Discipline; Engineering; Etiology; Gene Expression; Generations; Genetic Engineering; Home environment; Homologous Gene; Host Defense; Host resistance; Human; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Intravenous; Klebsiella pneumoniae; Length; Length of Stay; Lung; Lung diseases; Lung infections; Melioidosis; Modeling; Morbidity - disease rate; Mus; Nosocomial pneumonia; Organism; Pneumonia; Proteins; Public Health; Reporting; Research Personnel; Resistance; Respiratory Tract Infections; Route; Site; Solid Neoplasm; Southeastern Asia; System; Testing; Therapeutic; antimicrobial peptide; biothreat; cancer immunotherapy; carbapenem resistance; cathelicidin; chimeric antigen receptor T cells; cytokine; extracellular; flexibility; improved; improved outcome; in vivo; innovation; macrophage; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; pathogen; resistant strain; respiratory; therapy resistant

PROJECT SUMMARY Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Increasing antimicrobial resistance among common agents of bacterial pneumonia necessitates the development of new therapeutic strategies. In this project, we focus on two resistant pathogens that are public health threats. Burkholderia pseudomallei (BP) is a common etiology of pneumonia (pneumonic melioidosis) in Southeast Asia and northern Australia. Pneumonic melioidosis is lethal in 22-50% of cases despite treatment. BP is a facultative intracellular pathogen that is inherently resistant to many antibiotics and requires prolonged courses of therapy. Klebsiella pneumoniae (KP) is an extracellular pathogen that is a well known cause of community- and healthcare-associated pneumonia. KP has become increasingly resistant to carbapenems and third generation cephalosporins. Infections caused by resistant strains of KP are difficult to treat, prolong hospital stays, and are associated with high mortality. BP and KP are representative of the urgent need to develop new therapies to treat resistant lung infections. This project brings together three investigators from distinct disciplines to tackle this challenge. Drs. West and Skerrett are established researchers in pulmonary host defense against bacterial lung infections. They have created murine models of bacterial respiratory infection including BP (and surrogate organism, B. thailandensis) infection and KP. These bacterial respiratory infection models have been used to investigate host and bacterial factors and to evaluate therapeutics. Dr. Crane, a cancer immunotherapy researcher, has developed a novel and flexible system to create genetically engineered macrophages (GEMs) to produce a range of secreted proteins over a month in vitro or in vivo. Administered intravenously to mice, GEMs accumulate at high levels in the lungs for at least 4 days. Others have reported that airway delivery of macrophages results in durable localization of these cells within the lungs for months. Thus, intravenous or pulmonary delivery of GEMs may be a novel, versatile therapeutic strategy against lung infections. The central hypothesis of this proposal is that GEMs that produce pro-inflammatory and/or antimicrobial peptides and home to the site of infection can augment host resistance to respiratory infections caused by pathogens such as BP and KP. This hypothesis will be tested as follows: Aim 1. Develop and test GEMs with enhanced bacterial killing functions that produce the cytokine interleukin 12 (IL-12) or antimicrobial peptide CRAMP (the mouse homolog of human cathelicidin). Aim 2. Define localization and the inflammatory responses induced by IL-12- or CRAMP-expressing GEMs adoptively transferred in vivo. Aim 3. Determine whether the adoptive transfer of IL-12- or CRAMP-expressing GEMs augments resistance to acute bacterial pneumonia caused by B. thailandensis or K. pneumoniae. This innovative project tests two novel and potentially synergistic therapies for resistant yet distinct pathogens causing pneumonia. Moreover, the highly adaptable and tunable GEM platform is potentially very relevant to a wide variety of other lung infections and lung diseases.

项目摘要 细菌性肺炎是全球发病率和死亡率的主要原因。增加抗菌素 细菌性肺炎常见药物的耐药性需要开发新的治疗性 策略。在这个项目中，我们专注于两种抗性病原体，这些病原体是公共卫生威胁。 Burkholderia 假allei（BP）是东南亚和 北澳大利亚。尽管有治疗，但在22-50％的病例中，肺炎黑胶质病具有致命性。 BP是兼职 细胞内病原体固有地对许多抗生素具有抗药性，需要长时间的治疗方法。 肺炎克雷伯菌（KP）是一种细胞外病原体，是社区和社区的众所周知的原因 医疗保健相关的肺炎。 KP已经越来越抗碳青霉烯和第三代 头孢菌素。由KP抗性菌株引起的感染很难治疗，延长医院住院，并且是 与高死亡率有关。 BP和KP是迫切需要开发新疗法的代表 治疗抗性肺部感染。该项目汇集了来自不同学科的三名调查员来解决 这个挑战。博士。 West和Skerrett是针对细菌的肺部宿主防御的成熟研究人员 肺部感染。他们创建了细菌呼吸道感染的鼠模型，包括BP（和替代物 有机体，泰国芽孢杆菌）感染和KP。这些细菌呼吸道感染模型已用于 研究宿主和细菌因素并评估治疗剂。 Crane博士，一种癌症免疫疗法 研究人员开发了一种新颖而灵活的系统来创建基因工程的巨噬细胞（GEMS） 在一个月的体外或体内产生一系列分泌的蛋白质。对小鼠静脉内施用， 宝石在肺部高水平累积至少4天。其他人报告说，气道的交付 巨噬细胞导致这些细胞在肺部内持久定位数月。因此，静脉注射或 宝石的肺输送可能是针对肺部感染的新型，多才多艺的治疗策略。中央 该提议的假设是产生促炎和/或抗菌肽的宝石以及 感染部位的故乡可以增强宿主抵抗因病原体引起的呼吸道感染的能力 作为BP和KP。该假设将被测试如下：AIM 1。用增强的开发和测试宝石 产生细胞因子白介素12（IL-12）或抗菌肽绞痛的细菌杀死功能（ 小鼠同源物的人cathelicidin）。 AIM 2。定义定位和炎症反应 IL-12-或表达抽筋的宝石在体内传递。目标3。确定是否收养 IL-12-或表达绞痛的宝石的转移增强了对急性细菌性肺炎的抗性 B.泰国人或K.肺炎。这个创新的项目测试了两种小说且潜在的协同疗法 对于耐药性而不同的病原体引起肺炎。而且，高度适应性和可调的宝石 平台可能与多种其他肺部感染和肺部疾病非常相关。